The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response
The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response
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DOI：
10.1194/jlr.m900216-jlr200
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发表时间：
2009-12-01
影响因子：
6.5
通讯作者：
Austin, Richard C.
中科院分区：
文献类型：
--
作者：
Basseri, Sana;Lhotak, Sarka;Austin, Richard C.
最近的研究表明肥胖与内质网（ER）应激之间存在联系。内质网稳态的扰动会导致内质网应激和未折叠蛋白反应 (UPR) 的激活。脂肪细胞分化有助于体重增加，我们已经证明 ER 应激/UPR 激活的标志物，包括 GRP78、磷酸化 eIF2 α 和剪接的 XBP1，在脂肪形成过程中上调。鉴于这些发现，本研究的目的是确定化学伴侣 4-苯基丁酸酯 (4-PBA) 减弱 UPR 活化是否会抑制脂肪生成。在分化培养基存在的情况下，将 3T3-L1 前脂肪细胞暴露于 4-PBA 会降低 ER 应激标记物的表达。伴随着 UPR 激活的抑制，4-PBA 导致脂肪生成减弱（通过脂质积累和脂联素分泌来测量）。与这些体外研究结果一致，与单独高脂肪饮食组相比，喂食补充有 4-PBA 的高脂肪饮食的雌性 C57BL/6 小鼠体重增加显着减少，并且脂肪垫质量减少。此外，补充 4-PBA 可以降低脂肪组织中 GRP78 的表达，并降低血浆甘油三酯、葡萄糖、瘦素和脂联素水平，而不会改变食物摄入量。总而言之，这些结果表明 UPR 激活有助于脂肪生成，并且用 4-PBA 阻断其激活可防止小鼠脂肪细胞分化和体重增加。-Basseri, S.、S. Lhotak、A. M. Sharma 和 R. C. Austin。化学伴侣 4-苯基丁酸酯通过调节未折叠蛋白反应来抑制脂肪生成。 J.脂质研究。 2009。50：2486-2501。
Recent studies have shown a link between obesity and endoplasmic reticulum (ER) stress. Perturbations in ER homeostasis cause ER stress and activation of the unfolded protein response (UPR). Adipocyte differentiation contributes to weight gain, and we have shown that markers of ER stress/UPR activation, including GRP78, phospho-eIF2 alpha, and spliced XBP1, are upregulated during adipogenesis. Given these findings, the objective of this study was to determine whether attenuation of UPR activation by the chemical chaperone 4-phenylbutyrate (4-PBA) inhibits adipogenesis. Exposure of 3T3-L1 preadipocytes to 4-PBA in the presence of differentiation media decreased expression of ER stress markers. Concomitant with the suppression of UPR activation, 4-PBA resulted in attenuation of adipogenesis as measured by lipid accumulation and adiponectin secretion. Consistent with these in vitro findings, female C57BL/6 mice fed a high-fat diet supplemented with 4-PBA showed a significant reduction in weight gain and had reduced fat pad mass, as compared with the high-fat diet alone group. Furthermore, 4-PBA supplementation decreased GRP78 expression in the adipose tissue and lowered plasma triglyceride, glucose, leptin, and adiponectin levels without altering food intake. Taken together, these results suggest that UPR activation contributes to adipogenesis and that blocking its activation with 4-PBA prevents adipocyte differentiation and weight gain in mice.-Basseri, S., S. Lhotak, A. M. Sharma, and R. C. Austin. The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response. J. Lipid Res. 2009. 50: 2486-2501.